Project description:Metabolic alterations and direct cell-cell interactions in the tumor microenvironment (TME) affect the prognostic molecular landscape of tumors; thus, it is imperative to investigate metabolic activity at the single-cell level rather than in bulk samples to understand the high-resolution mechanistic influences of cell-type specific metabolic pathway alterations on tumor cells. To investigate tumor metabolic reprogramming and intercellular communication at the single-cell level, we analyzed eighty-four metabolic pathways, seven metabolic signatures, and tumor-stroma cell interaction using 21,084 cells comprising gastric cancer and paired normal tissue. High EMT-score cells and stem-like subtype tumors showed elevated glycosaminoglycan metabolism, which was associated with poor patient outcome. Adenocarcinoma and macrophage cells had higher reactive oxidative species levels than the normal controls; they largely constituted the highest stemness cluster. They were found to reciprocally communicate through the common ligand RPS19. Consequently, ligand-target regulated transcriptional reprogramming resulted in HS6ST2 expression in adenocarcinoma cells and SERPINE1 expression in macrophages. Gastric cancer patients with increased SERPINE1 and HS6ST2 expression had unfavorable prognoses, suggesting these as potential drug targets. Our findings indicate that malignant stem-like/EMT cancer cell state might be regulated through reciprocal cancer cell-macrophage intercellular communication and metabolic reprogramming in the heterogeneous TME of gastric cancer at the single-cell level.
Project description:Gastric cancer is an extremely common digestive tract tumor. The promotion and application of standardized therapy, treatment scheme optimization, and development of new targeted drugs and immunotherapies have improved gastric cancer survival somewhat. However, gastric cancer prognosis generally remains non-optimistic. Immune checkpoint inhibitors (ICI) have gradually become a new choice for gastric cancer treatment and can prolong the survival of some patients. Among them, high-microsatellite instability, Epstein-Barr virus-positive status, or high-tumor mutational burden patients with gastric cancer may be the potential population to benefit from immunotherapy. Nevertheless, there remains a lack of unified and effective predictive markers. Accordingly, this review mainly focused on the possible predictive biomarkers of anti-PD-1/PD-L1 in gastric cancer treatment. Furthermore, the application of anti-PD-1/PD-L1 therapy-related clinical trials on gastric cancer is discussed. The current findings suggest that immunotherapy is a promising application in gastric cancer treatment. Therefore, combining immunotherapy and other therapies may be the trend in the future. Nevertheless, exploring biomarkers to predict ICI response remains a major challenge.
Project description:Macrophages are critical mediators of tissue homeostasis, with the function of tissue development and repair, but also in defense against pathogens. Tumor-associated macrophages (TAMs) are considered as the main component in the tumor microenvironment and play an important role in tumor initiation, growth, invasion, and metastasis. Recently, metabolic studies have revealeded specific metabolic pathways in macrophages are tightly associated with their phenotype and function. Generally, pro-inflammatory macrophages (M1) rely mainly on glycolysis and exhibit impairment of the tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS), whereas anti-inflammatory macrophages (M2) are more dependent on mitochondrial OXPHOS. However, accumulating evidence suggests that macrophage metabolism is not as simple as previously thought. This review discusses recent advances in immunometabolism and describes how metabolism determines macrophage phenotype and function. In addition, we describe the metabolic characteristics of TAMs as well as their therapeutic implications. Finally, we discuss recent obstacles facing this area as well as promising directions for future study.
Project description:Immunotherapy benefits selected cases of gastric cancer (GC), but the correlation between biomarkers and prognosis is still unclear. Fifty-two patients with GC who underwent immunotherapy were enrolled from June 2016 to December 2020. Their clinical features and biomarkers-microsatellite instability-high (MSI-H), programmed cell death ligand 1 (PD-L1) combined positive score (CPS), and Epstein-Barr encoding region (EBER)-were analyzed. Eight patients had MSI-H, five patients had EBER, 29 patients had CPS ≥ 1, and 20 patients had no biomarker. The overall response rates (ORRs) of the MSI-H, EBER, PD-L1 CPS ≥ 1, and all-negative group were 75%, 60%, 44.8%, and 15%, respectively. Compared with that of the all-negative group, progression-free survival (PFS) was better in the MSI-H (p = 0.018), CPS ≥ 5 (p = 0.012), and CPS ≥ 10 (p = 0.006) groups, but not in the EBER (p = 0.2) and CPS ≥ 1 groups (p = 0.35). Ten patients had combined biomarkers, CPS ≥ 1 with either MSI-H or EBER. The ORRs were 66.7% for CPS ≥ 1 and MSI-H and 75% for CPS ≥ 1 and EBER. PFS was better in patients with combined biomarkers (p = 0.01). MSI-H, EBER, and CPS are useful biomarkers for predicting the efficacy of immunotherapy.
Project description:Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33 on PM-associated TIME. Immunocompetent mice were used to investigate the role of IL-33 in development of abdominal dissemination and host outcome. Murine (m) and human (h) gastric cancer cells were tested for their response to IL-33 using qRT-PCR, flow cytometry, and immunofluorescence. The survival was significantly prolonged in patients with high IL-33 mRNA expression. Intraperitoneal administration of IL-33 could induce the celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 (GATA3) signaling pathway. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) showed a synergistic antitumor effect. Intraperitoneal administration of IL-33 inducing local inflammatory milieu provided a novel approach for treating metastatic peritoneal malignancies, which was combined with TAM reprogramming to reshape TIME to achieve better treatment efficacy.
Project description:Tunneling nanotubes (TNTs) are F-actin-based membrane tubes, and can form between cultured cells and within vital tissues. TNTs mediate intercellular communications that range from electrical signaling to the transfer of organelles. Following peripheral nerve injury, the orchestrated intercellular communications among neural and non-neural cells are required for effective nerve regeneration. It remains unknown whether TNTs exist between neural cells in the peripheral nerve system and how TNTs affect neural regeneration. To address these interesting questions, we investigated the transfer of neurotropic factors, membrane protein, cytoplasmic protein, mitochondria and RNA in functional TNTs formed between cultured Schwann cells (SCs). TNT-like structures were increased not only in cultured SCs after exposure to serum depletion but also in longitudinal sections of proximal sciatic nerve stump harvested after rat peripheral nerve transection. Meanwhile, downregulation of Rab8a or Rab11a in cultured SCs inhibited the formation of functional TNTs and vesicle transfer and led to decrease in cell migration, increase in SCs apoptosis. Likewise, knockdown of Rab8a or Rab11a in primary SCs also suppressed axonal outgrowth from co-cultured dorsal root ganglion (DRG) neurons. Overall, our results suggested that the gene of Rab8a or Rab11a might be involved in the formation of TNTs structures in the peripheral nerve system, while TNTs structures were likely to affect peripheral nerve regeneration through the regulation of neural cell communications.
Project description:In the age of bioinformatics and with the advent of high-powered computation over the past decade or so the landscape of biomedical research has become radically altered. Whereas a generation ago, investigators would study their "favorite" protein or gene and exhaustively catalog the role of this compound in their disease of interest, the appearance of omics has changed the face of medicine such that much of the cutting edge (and fundable!) medical research now evaluates the biology of the disease nearly in its entirety. Couple this with the realization that kidney cancer is a "metabolic disease" due to its multiple derangements in biochemical pathways [1, 2], and clear cell renal cell carcinoma (ccRCC) becomes ripe for data mining using multiple omics approaches.
Project description:Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.
Project description:By targeting the tumor microenvironment to stimulate antitumor immunity, immunotherapies have revolutionized cancer treatment. However, many patients do not respond initially or develop secondary resistance. Based on the limited resources in the tumor microenvironment and competition between tumor and immune cells, the field of immune metabolism has produced extensive knowledge showing that targeting metabolism could help to modulate antitumor immunity. However, among all the different potentially targetable metabolic pathways, it remains unclear which have more potential to overcome resistance to immune checkpoint inhibitors. Here, we explore metabolic reprogramming in cancer cells, which might inhibit antitumor immunity, and strategies that can be used to favor the antitumor response.